Tomorrow the 2nd DIPG Collaborative Symposium begins in Cincinnati. This two track program brings together doctors and researchers in one track and foundations and parents in another (with a potential networking dinner Friday evening). The goal is to be able to "efficiently fund and inspire diffuse intrinsic pontine glioma cancer research in hopes of finding a wider cure for cancer". This year there is expected to be approximately 140 from 7 countries. With the diverse agenda with international speakers on the forefront of DIPG research, I suspect it will be an exciting place to be for those interested in pediatric diffuse intrinsic pontine glioma.
The 2011 DIPG Collaborative Symposium brought about some substantive advances in the infrastructure critical for DIPG research including the DIPG Registry, the DIPG Preclinical Consortium, and the DIPG Genomics Repository.
This meeting starts Friday morning with a Keynote Lecture from Canadian geneticist and researcher, Nada Jaboda MD PhD. Although the topic has not been release I am thinking- H3.3,K27M and epigenetics. To get a taste of the work she has been doing in unravelling pediatric vs adult astrocytomas (including DIPG) there is a NYU Grand Rounds titled "Rewiring the Epigenome in Pediatric and Young High Grade Astrocytomas" presented on December 18, 2012. (click here to watch the video) This work has the potential to change how we approach and treat DIPGs.
The meeting continues with a update of research funded through the collaborative and the Cure Starts Now:
Preclinica/Traslantional
* Xiao-Nan Li(Baylor)- an oncolytic picorna virus in a DIPG xenograft mouse model.
* Oren Becher (Duke)- systemic and direct delivery of a PDFGR-alpha antibody.
* Suzanne Baker (St Jude)- establishment and characterization of DIPG renewable tissue resources
* Patricia Baxter (Texas)- Novel BMI-1 inhibitors in brainstem xenograft mouse models.
* Michele Monje (Stanford)- combined targeted therapy for cellular subpopulations in DIPG.
Clinical
Mark Souweidane (Cornell)- CED trial update
multiple- DIPG Registry update
This will be followed by various other sessions especially revolving around biopsy, biologic understanding of DIPG and current trends in clinical trials. One of the most anticipated things for me is the Xerecept session on Friday afternoon. It has been years of waiting for this drug to see if it can decease the suffering caused by steroids in so many DIPG children (click here for video). Hopefully something substantive will come from this session.
The other track- the parents and foundation track- will meet primarily on Saturday to discuss the Collaborative objectives, structure, prior efforts and success.
The event will culminate with a Once in a Lifetime Gala which looks to be spectacular (sold out- 1200 seat). This year's three ring circus them features the Cincinnati Circus and Nik Walenda.
Reference:
DIPG Collaborative Symposium Meeting Agenda
https://csn.donordrive.com/assets/csn/files/$cms$/100/2097.pdf
DIPG Preclinical Consortium-
http://pptiohsu.blogspot.com/2011/12/open-science-forum-dipg-preclinical.html
DIPG Registry-
http://www.dipgregistry.org/
Thursday, May 2, 2013
Wednesday, May 1, 2013
Voices on Pediatric DIPG Biopsy- Mark Kieran MD PhD
ASCO 2012 Education Session Presentation
The third speaker on the 2012 ASCO session was Mark Kieran from Boston presenting "Identification of Novel Biologic Targets in the Treatment of Newly Diagnosed Diffuse Intrinsic Pontine Glioma". Certainly Dr Kieran has been enduring in his passionate belief that non-treated tissue is going to be critical to the understanding and hopefully cure of DIPG. He has worked much of the past decade to bring the standard of care for typical pediatric DIPG in line with advancements in neurosurgical techniques and cancer molecular biology research. The video announcing that DIPG biopsy would be an educational session at 2012 ASCO much have provided a sense of satisfaction that this issue had reached prominence enough to be discussed at a significant cancer meeting. (click here to watch announcement video)
The first video I saw of Dr Kieran discussing this advancements in neurosurgery and cancer molecular biology research that makes DIPG biopsy possible and critical in understanding pediatric DIPGs was back in 2009. The first international DIPG conference in Barcelona, Spain sponsored by the Alicia Pueyo Foundation included a presentation on this issue. (click here for video) The 2012 video shows how far we have come in the DIPG community as well as with cancer molecular biology.
Dr Kieran points out that the understanding DIPG biology is in it's infancy. Few existing publications are on non-treated (biopsy specimens). Treatment has the potential of significantly altering the genomics of a tumor. However, there have been some consistencies:
* P53 loss/mutation is present in a significant number of tumors.
* The RTK-Ras-PI3K-Akt pathway is altered in a number of tumors.
* PTEN loss might mean that mTOR might be a target.
* Hedgehog-dependent cancer stem cells might be a target.
Regardless of the ultimate biology of DIPG, we can definitely say that DIPG is different from both adult and pediatric high grade gliomas. Treatment for kids with DIPG can not be based on these other tumors.
There is a caveat- just finding drugable targets might not alter the outcome with DIPG. So for this approach has not changed the prognosis in adult GBMs despite a huge amount of available tissue. We are at the beginning. We don't know yet. There is hope and optimism that this is a start.
References:
From boos to hope: Challenging the dogma about deadly brain stem gliomas
http://childrenshospitalblog.org/from-boos-to-hope-challenging-the-dogma-about-deadly-brain-stem-gliomas
Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma
http://www.ncbi.nlm.nih.gov/pubmed/22190243
ASCO 2012 Education Session Presentation
Critical oncogenic mutations in newly diagnosed pediatric diffuse intrinsic pontine glioma
http://www.ncbi.nlm.nih.gov/pubmed/22190243
Tuesday, April 30, 2013
Voices on Pediatric DIPG Biopsy- Nicholas Foreman MD ChB
ASCO 2012 Educational Session Presentation
"If the the definition of insanity is doing the same useless thing with the same outcome, this is it."
....Dr Nick Foreman speaking on the negative results on dozens of trials in DIPGs with no biologic knowledge of the tumor
Dr Nick Foreman, director of the pediatric neuro-oncology program at Denver Children's, presented the second lecture at the 2012 ASCO educational meeting "Pontine Gliomas in Children:To Biopsy or Not to Biopsy". Dr Foreman along with his colleague, neurosurgeon Dr Michael Handler, actively and aggressively challenged medicine's standard practice of not preforming biopsies in 10% of children with brain tumors when that tumor (DIPG) has been almost always fatal and no trial has shown any benefit for the tumor. They argued that it was really unethical to continue to subject these patients to phase 1 trials to obtain toxicity and dosage data when one could not show any benefit from the dozens of trials previously. These two physicians worked to have the American Society of Neurosurgery reverse the standard practice of not preforming biopsies for DIPG children.
This 16 1/2 minute presentation is a personal account of the resistance encountered when developing DIPG research that stemmed from work done in 2004 in biopsies of pediatric supratentorial GBMs. The 2004 work lead to a 2007 IRB proposal in which 10 children with DIPGs were to be biopsied (with parental consent) without treatment based on those biopsies. This was pretty much exactly what France had already done and published results with no mortality and transient morbidity. However, the local IRB could not make a decision resulting in an FDA hearing on the topic. The results of the FDA panel was mixed so the initial proposal of 10 children being biopsied was rejected in favor of the current upfront biopsy trial that is underway.
Now that we have the biopsy trial open in the US and 2011 Consensus Conference on Pediatric Neurosurgery specifically stated a standard regarding biopsy of typical pediatric DIPGs within clinical trials, we may now be past much of the controversy of the past decade. Still, I think it is important to know the traumatic, tragic history of how this stagnated DIPG research.
Dr. Foreman ends pondering a question on whether we "missed the boat" for DIPG children by failing to openly recognize that in experienced hands DIPG biopsy is not more dangerous than in other areas of the brain.
If the majority understood that the 1993 paper recommending "routine biopsies be relegated to history" was referring to MRI's accuracy of diagnosis and not on DIPGs surgical risk/safety, could we have moved faster in the current age of cancer molecular biology to have known about such abnormalities as the histone mutation much earlier. Perhaps we could have been further along on a cure.
References:
Nicholas Foreman, Pediatric Neuro-Oncologist
Interpretation of magnetic resonance images in diffuse intrinsic pontine glioma: a survey of pediatric neurosurgeons
Slides of Dr Foreman's presentation in 2009 to the FDA
Magnetic resonance scans should replace biopsies for the diagnosis of diffuse brainstem gliomas: a report from the Children's Cancer Group
Monday, April 29, 2013
Voices on Pediatric DIPG Biopsy - Stephanie Puget MD PhD
ASCO 2012 Educational Session Presentation
One of the most controversial subjects in pediatric DIPGs over the last decade has been the biopsy issue. This has been the topic of discussion in private, editorials and even an FDA open hearing. At the 2012 ASCO meeting in Chicago there was an educational meeting chaired by Mark Kieran MD PhD entitled "Pontine Gliomas in Children:To Biopsy or Not to Biopsy". To me the greatest thing about this session is that it was taped and made available on the internet. This allows for those who were not in Chicago last year for ASCO to have a better understanding directly from some of the key international figures regarding this extremely important matter.
Stephanie Puget MD PhD, a French neurosurgeon, started the session with a 20 minutes presentation on "Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?" Dr Puget is a central figure in the landmark French DIPG clinical trial with upfront biopsy. Since the 2007 publication it seems that Dr Puget has had speaking engagements on both sides of the Atlantic to discuss DIPG biopsy. This was the first time though that I was able to actually hear her speak.
Dr. Puget started her talk with five questions.
1) Is biopsy needed for a DIPG diagnosis?
2) If not, why do biopsy for DIPG?
3) Can DIPG biopsy be safely preformed?
4) Can DIPG biopsy be preformed by everyone?
5) What can be done with the biopsy specimens?
The short answers-
1) No, it is made by MRI in conjunction with clinical symptoms.
2) Analysis of the tumors may lead to relevant biomakers and hopefully better treatment.
3) Yes.
4) No.
5) Allows for molecular studies (including whole genome sequencing and mutational analysis) and cell lines (of which they had 5 stem cell lines a the time).
During the presentation she reviewed the results of the French Biopsy experience. From 2002 to 2012, 92 biopsies were preformed with no mortality and only 5 patients experience morbidity. Four of these patients had transient problems including cranial nerve palsies or weakness. One child had a permanent hemiparesis but also was found to have disease progression. She said "it could be considered as safe as a stereotactic biopsy in the supra-tentorial space in a well-trained neurosurgical team".
She also addressed a few technical considerations: frame versus frameless surgery, choosing a route and choosing a biopsy site. Please note at approximately 14:30 minutes there are real videos of biopsy in children. At 18:30 minutes the size of the biopsy samples is shown as well as pre and post procedure MRIs.
For those interested in the pediatric DIPG biopsy issue, this is a very informative 20 minute presentation from someone who as been on the frontline.
Reference:
Is Biopsy Safe in Children with Newly Diagnosed Diffuse Intrinsic Pontine Glioma?
Stephanie Puget MD PhD
http://meetinglibrary.asco.org/content/66763
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